Published online before print August 27, 2009, doi: 10.1161/CIRCRESAHA.109.202713
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Submitted on March 16, 2009
Revised on August 16, 2009
Accepted on August 18, 2009
Negative Action of Hepatocyte Growth Factor/c-Met System on Angiotensin II Signaling via Ligand-Dependent Epithelial Growth Factor Receptor Degradation Mechanism in Vascular Smooth Muscle Cells
Fumihiro Sanada ;
From the Departments of Clinical Gene Therapy (F.S., Y.T., K.I., J.A., K.O., H.K., R.M.); Geriatric Medicine and Nephrology (Y.T., K.I., J.A., K.O., H.K.); and Pharmacology (T.D.), Osaka University Graduate School of Medicine; Division of Cardiology, Hematology and Endocrinology/Metabolism (F.S., Y.A.), Niigata University Graduate School of Medical and Dental Science; and Department of Advanced Clinical Science and Therapeutics (N.K.), Graduate School of Medicine, The University of Tokyo, Japan.
* To whom correspondence should be addressed. E-mail: taniyama{at}cgt.med.osaka-u.ac.jp.
Objective: To elucidate the mechanism how HGF and its receptor c-Met reduces angiotensin II (Ang II)–induced inflammation.
Methods and Results: HGF reduced Ang II–induced vascular smooth muscle cell growth and inflammation by controlling translocation of SHIP2 (Src homology domain 2–containing inositol 5'-phosphatase 2), which led to Ang II–dependent degradation of epithelial growth factor receptor. Moreover, the present study also revealed a preventive effect of HGF on atherosclerotic change in an Ang II infusion and cuff HGF transgenic mouse model.
Conclusions: These data suggest that the HGF/c-Met system might regulate extrinsic factor signaling that maintains the homeostasis of organs.
Key words: hepatocyte growth factor • c-Met • SHIP2 • epithelial growth factor receptor • neointimal formation